Participation in activities and secondary health complications among persons aging with traumatic spinal cord injury.

STUDY DESIGN: Cross-sectional study. OBJECTIVES: To describe participation in activities and explore the relationship with secondary complications among persons aging with a traumatic spinal cord injury (SCI). SETTING: A regional SCI outpatient center in Sweden. METHODS: Data were collected through a phone survey, which included 10 activities from the instrument PARTS/M-v3 (PARTicipation Survey/Mobility version-3) together with data from the participants' medical records. Cross-tabulation and χ2 were used for data analysis. RESULTS: In this study, 121 persons matched the inclusion criteria and the final study sample comprised 73 participants (60% response rate): 55 men and 18 women. Mean age was 63.7±9.4 years, and mean time since injury was 36.3±9.2 years. Regardless of duration of SCI, all 73 participated in dressing, bathing and leisure activities. Women reported better health than men. Particularly for those who lived 36-55 years after injury; increasing pain, fatigue, spasticity and decreased muscle strength were negatively affecting participation in activities, especially exercise and active recreation. Additionally, a need to save strength/energy was also a reason for not participating in the activities. Perceived future support and concerns in relation to personal assistance, assistive devices and rehabilitation was also reported. CONCLUSION: Increasing secondary health complications and a need to save strength/energy influenced participation in activities. Laws and/or governmental policies regarding personal assistance and assistive devices did not always support participation in activities. Interventions should aim to create a balance among activities in everyday life.

Morphine-induced delay of normal cell death in the avian ciliary ganglion.

Repeated administration of morphine in increasing doses delayed normal cell death in the ciliary ganglion of the chick embryo; the effect was completely blocked by naloxone. Survival of spinal motoneurons was not affected. Morphine also inhibited potassium-stimulated synthesis of acetylcholine in ganglion cells cultured with muscle, suggesting that morphine can influence neurotransmission. Morphine's effect on cell death may be due to an inhibition of transmission at the neuromuscular junction, but opiates may also directly affect cell death. Although it is now known whether the endogenous opiates in the ciliary ganglion influence neuronal survival during embryogenesis, exogenous opiates can affect normal cell death in the autonomic nervous system.

Developmental switch in the pharmacology of Ca2+ channels coupled to acetylcholine release.

The pharmacological specificity of Ca2+ channel-secretion coupling in acetylcholine (ACh) and somatostatin (SOM) release was studied in the chick eye choroid neuromuscular junctions and in dissociated ciliary ganglion (CG) neurons. ACh secretion changes in development from stage (St) 40, when release is dihydropyridine (DHP) and partially omega-conotoxin (omega-CgTX) sensitive, to posthatch, when release is insensitive to DHPs but sensitive to omega-CgTX. St 40 CG neurons cultured with striated muscle have release properties similar to those of St 40 iris and choroid but different from those of St 34 neurons, which are neither DHP nor omega-CgTX sensitive. SOM (also coreleased from posthatch choroid terminals) can inhibit ACh release in both posthatch and St 40 choroids, suggesting that the SOM receptor interacts with both DHP-sensitive and -insensitive channels.

Effect of a multidisciplinary intervention on medication compliance in elderly patients with congestive heart failure.

PURPOSE: The objectives of this investigation were to prospectively assess medication compliance rates in elderly patients with congestive heart failure, to identify factors associated with reduced compliance, and to evaluate the effect of a multidisciplinary treatment approach on medication adherence. PATIENTS AND METHODS: A total of 156 patients > or = 70 years of age (mean, 79.4 +/- 6.0; 67% female, 65% nonwhite) hospitalized with congestive heart failure were evaluated prospectively. Prior to discharge, patients were randomized to the study intervention (n = 80) or conventional care (n = 76). The intervention consisted of comprehensive patient education, dietary and social service consultations, medication review, and intensive postdischarge follow-up. Detailed data were collected on all prescribed medications at the time of discharge, and compliance was assessed by pill counts 30 +/- 2 days later. RESULTS: The overall compliance rate during the first 30 days after discharge was 84.6 +/- 15.1% (range, 23.1-100%). Compliance was 87.9 +/- 12.0% in patients randomized to the study intervention, compared with 81.1 +/- 17.2% in the control group (P = 0.003). A compliance rate of > or = 80% was achieved by 85.0% of the treatment group versus 69.7% of the control group (P = 0.036). By multivariate analysis, assignment to the treatment group was the strongest independent predictor of compliance (P = 0.008). Other variables included in the model were Caucasian race (P = 0.044) and not living alone (P = 0.09). CONCLUSIONS: A multidisciplinary treatment strategy is associated with improved medication compliance during the first 30 days following hospital discharge in elderly patients with congestive heart failure. Improved compliance may contribute to improved outcomes in these patients.

Membrane delimited and intracellular soluble pathways in the somatostatin modulation of ACh release.

The signal transduction cascade between the activation of the somatostatin (SOM) receptor and modulation of transmitter release was study using Acetylcholine (Ach) release measurements and patch clamp recordings of Ca2+ current from acutely dissociated St 40 ciliary ganglion neurons. As in intact synapses, somal ACh release was blocked by 100 nM SOM or 100 microM dibutyril cGMP, and the SOM-mediated inhibition could be reversed by 10 microM 1-NAME (a selective inhibitor of nitric oxide synthase, NOS) or 100 microM Rp-8p-CPT-cGMPs (a selective inhibitor of a cGMP protein dependent kinase, PKG). In whole cell recordings, SOM inhibition of Ca2+ current rapidly relaxes to control levels but is sustained in perforated patch recordings which decreases cell dialysis. Inhibition of NOS or PKG in perforated patch recordings, however caused SOM effects to become transient again. We hypothesize that PKG alters the characteristics of the membrane-delimited G protein inhibition of Ca2+ current. Therefore SOM receptors trigger a membrane-delimited signal transduction cascade that is modulated by soluble messengers, converging on voltage activated Ca2+ channels. When both pathways are active together, SOM causes a sustained inhibition of neuronal Ca2+ current leading to a decrease in transmitter release.

Disability and rehabilitation research from policy to program. A personal perspective.

This article provides a description of the role of a research institute director in implementing policy, program, and management changes. The importance of modifying a peer review system to improve funding decisions is emphasized. The needs of individuals with disabilities for pragmatic solutions to their problems and the interests of the rehabilitation research community are discussed in the context of program development. The perspective is a personal review provided by a former Director of the National Institute on Disability and Rehabilitation Research.

Fluid bed granulation of a poorly water soluble, low density, micronized drug: comparison with high shear granulation.

A 2(4-1) fractional factorial design was used to evaluate the effect of various process variables in fluid bed granulation, on the physico-chemical properties of granule and tablet containing a high dose, poorly water soluble, low density, and micronized drug. The process variables studied were inlet air temperature, inlet air flow, spray rate of the binder solution, and atomization air pressure. Tablets with identical composition, weight, size and hardness were also manufactured in a high shear granulator and their physical properties were determined and compared with those produced by the fluidized bed granulation method. Except for the granule size distribution, other physical properties of granulations and tablets produced in a fluid bed granulator are independent of the selected process variables within the study range. Both atomization air pressure and spray rate of the binder solution had strong impact on granule size distribution. Irrespective of the process conditions used in the fluid bed granulation, granules from this process were more porous, less dense and more compressible than the granules from the high shear granulation process. Comparable tablet dissolution rates to those prepared by the optimized high shear granulation method can be achieved by selecting the appropriate process conditions in fluid bed granulation. These results suggest that wet granulation tablets of a high dose, poorly water soluble, low density, micronized drug can be manufactured using a fluidized bed granulation method, with comparable tablet dissolution rates to those produced with an optimized high shear granulation method.

[3H]acetylcholine synthesis in cultured ciliary ganglion neurons: effects of myotube membranes.

Avian ciliary ganglion neurons in cell culture were examined for the capacity to synthesize acetylcholine (ACh) from the exogenously supplied precursor, choline. Relevant kinetic parameters of the ACh synthetic system in cultured neurons were found to be virtually the same as those of the ganglionic terminals in the intact iris. Neurons were cultured in the presence of and allowed to innervate pectoral muscle; this results in an capacity for ACh synthesis. In particular, the ability to increase ACh synthesis upon demand after stimulation is affected by interaction with the target. This effect is shown to be an acceleration of the maturation of the cultured neurons. Lysed and washed membrane remnants of the muscle target were able to duplicate, in part, this effect of live target tissue on neuronal transmitter metabolism. Culture medium conditioned by muscle, and by the membrane remnants of muscle, was without significant effect. Thus, substances secreted into the medium do not play a major role in this interaction. Neurons cultured with either muscle or muscle membrane remnants formed large, elongate structures on the target membrane surface. These were not seen in the absence of the target at the times examined. This morphological difference in terminal-like structures may parallel the developmental increases in size and vesicular content of ciliary ganglion nerve terminals in the chick iris, and may relate to the increased ACh synthetic activity. The results suggest that direct contact with an appropriate target membrane has a profound, retrograde influence upon neuronal metabolic and morphological maturation.

The ICIDH-2: developments for a new era of outcomes research.

This article reviews the important concepts that led to the development of the International Classification of Impairments, Disabilities, and Handicaps (ICIDH), explicates the International Classification of Functioning and Disability (ICIDH-2), and discusses implications of the ICIDH-2 as a conceptual framework for outcome measures. The original ICIDH opened the door to include factors outside the traditional classification boundaries of disease, illness, and functional limitations that have framed the concept of disability. The new factors in the ICIDH-2 include a dimension for participation in social activities and a listing of environmental factors that are important for understanding the complexity of disability. The ICIDH-2 offers an opportunity for building a consensus on the terms used to describe disability and on the scope of factors to include in studying disability.

Somatostatin-induced inhibition of neuronal Ca2+ current modulated by cGMP-dependent protein kinase.

Neurotransmitter release is frequently regulated by peptides that modulate neuronal calcium channels. Whole-cell recordings show that the ion permeability and voltage dependence of these channels are controlled by a membrane-associated pathway involving GTP-binding proteins. Here we use perforated-patch recordings to show that, in addition to this pathway, the peptide somatostatin inhibits the calcium current in chick ciliary ganglion neurons by a second soluble pathway involving a cyclic GMP-dependent protein kinase (cGMP-PK). This somatostatin inhibition of Ca2+ current did not desensitize and was not characterized by the slowing of Ca(2+)-current activation (kinetic slowing) observed in whole-cell recordings. When cGMP-PK was inhibited, somatostatin inhibition of Ca2+ current resembled that observed with whole-cell recordings. cGMP agonists mimic the effect of somatostatin only in perforated patch recordings. An endogenous cGMP-PK therefore forms part of the mechanism by which somatostatin induces a sustained inhibition of neuronal calcium channels.

Opiate and peptide inhibition of transmitter release in parasympathetic nerve terminals.

Somatostatin, morphine, and opioids inhibit transmitter release at intact neuromuscular junctions between ciliary ganglion neurons and the choroidal smooth muscle of the chick eye. Somatostatin and morphine, however, have no effect on release from terminals on the striated muscle target of the ciliary ganglion, the iris. In neuronal terminals of both the choroid and the iris, a high-affinity Na+-dependent choline uptake-mediated ACh synthesis is present at hatching. Both tissues exhibit a basal release of 3H-ACh which is potentiated severalfold during a 5 minute incubation in 55 mM K+ Tyrodes. Fifty percent of the basal release and 100% of the stimulated release are Ca2+ dependent and probably mediated through N-like voltage-dependent Ca2+ channels. Co-incubation of the choroid with 10 microM morphine sulfate blocks approximately 90% of the stimulated release. The same effect is seen with 100 nM somatostatin, 10 microM dynorphin, and 100 microM met-enkephalin arginine phenylalanine. Preincubation of the excised choroid with pertussis toxin (200 ng/ml) reverses the inhibitory effects of both morphine and somatostatin. In contrast, 3H-ACh release from terminals in the striated iris is not affected by either morphine or somatostatin at micromolar levels. These results suggest that both opiate and somatostatin receptors are present in the choroid target and that they may act through a final common pathway to modulate ACh release via G proteins. Second messengers such as cyclic AMP or diacylglycerol do not appear to mediate these effects; neither increasing cAMP levels in terminals nor activation of protein kinase C affects evoked release or its inhibition by morphine or other neuromodulators. It is unclear whether endogenous neuromodulation occurs in this system, although somatostatin-like immunoreactivity can be demonstrated in terminals of choroid neurons.

Endogenous modulation of ACh release by somatostatin and the differential roles of Ca2+ channels.

The classical neurotransmitter acetylcholine (ACh) and the potential modulatory peptide somatostatin are colocalized in terminals of avian choroid neurons. We previously showed that exogenous somatostatin inhibits ACh release in the choroid coat (Gray et al., 1989b). In the present work we determine whether endogenous somatostatin plays a role in neuromodulation and what mechanisms are involved. To determine its role and its mode of secretion, voltage-sensitive Ca2+ channels in these terminals were identified pharmacologically using Ca2(+)-dependent K(+)-evoked ACh release. Release of the primary transmitter ACh was triggered in the presence of high K+ by Ca2+ influx primarily via dihydropyridine (DHP)-insensitive channels, while inhibition of ACh release occurred when L-type channels were activated by the DHP agonist Bay K 8644. The somatostatin antagonist cyclo(7-aminoheptanoyl-phe-D-trp-lys-thr (BZL)) (CyCam) blocks the inhibition of ACh release induced by the agonist Bay K 8644 and indicates that endogenous somatostatin may normally modulate ACh release. Additionally, nifedipine, a DHP antagonist, and pertussis toxin, known to antagonize somatostatin's effect on ACh release, both reverse the Bay K 8644 effect on ACh release. Although the release of labeled ACh in the first 3 min collection period was not significantly affected by CyCam or nifedipine alone, release in the first minute was enhanced by 50% in the presence of 10 microM nifedipine. Preincubation with CyCam alone also increased ACh release. These results support the hypothesis that endogenous somatostatin is physiologically released during the initial minute of depolarization in high K+ and that this release is mediated by DHP-sensitive Ca2+ channels.

Mortality risks of mentally retarded and mentally ill patients after a feeding gastrostomy.

Feeding gastrostomy procedures were performed on 9 mentally ill and 30 mentally retarded, institutionalized patients. The postoperative mortality was 0 percent (0/9) for the mentally ill and 13 percent (4/30) for the mentally retarded patients. Mortality within 1 year after the operation was 11 percent (1/9) for the mentally ill and 33 percent (10/30) for the retarded patients. This study revealed three important factors that affect mortality risks: the identification and elimination of a gastroesophageal reflux before surgery, the monitoring and improvement of the nutritional status both before and after surgery, and the evaluation and treatment of respiratory problems both before and after surgery. If care in these areas is improved, then the mortality risks for retarded patients will decrease.

Solubility enhancement of a bisnaphthalimide tumoricidal agent, DMP 840, through complexation.

The purpose of this research was to enhance the aqueous solubility of DMP 840 by complexation with water-soluble and nontoxic agents, and to understand the nature of the interactions involved in complex formation using nuclear magnetic resonance (1H-NMR). The solubility of DMP 840 in water, saline, acetate buffers, and cosolvent mixtures was determined by high-performance liquid chromatography, and the effect of nicotinamide and pyridoxine concentrations on the solubility of DMP 840 was examined by the phase solubility method. 1H-NMR spectra were acquired in deuterated acetate buffer at 400 MHz on a Varian Unity-400 spectrometer. The aqueous solubility of DMP 840 was sensitive to the presence of chloride and acetate anions in solution, and did not improve in the presence of cosolvents. The use of the nontoxic and water-soluble complex-forming agents nicotinamide and pyridoxine, however, resulted in a linear increase in the aqueous solubility of DMP 840 with both ligands. The solubilization appears to be due to formation of 1:1 complexes between DMP 840 and the bioorganic ligands. The complexation constants were 15.57 M-1 for the DMP 840:nicotinamide complex and 13.36 M-1 for the DMP 840:pyridoxine complex. The NMR results indicate that the interaction is a result of vertical or plane-to-plane stacking and the complexation constants were in agreement with that obtained by phase solubility. The results suggest that the aqueous solubility of a poorly water soluble drug substance such as DMP 840 can be significantly enhanced by its complexation with water-soluble and nontoxic agents.

Degradation kinetics of DMP 777, an elastase inhibitor.

PURPOSE: The objective was to evaluate the degradation profile of the elastase inhibitor DMP 777 and lay the foundation for formulation development. METHODS: The pKa was determined by potentiometric titration in mixed-aqueous solvents. The degradation kinetics were studied as a function of pH, buffer concentration, ionic strength, methanol concentration and temperature using a stability-indicating HPLC assay. The degradation products were identified by LC-MS, NMR, and by comparison with authentic samples. RESULTS: The pKa for the protonated piperazine nitrogen was estimated to be 7.04. The pH-rate profile is described by specific acid-, water-, and specific base-catalyzed pathways. The pH of maximum stability is in the range of 4 to 4.5 where water is the principal catalyst in the reaction. Buffer catalysis, primary salt effects and medium effects were observed. The proposed mechanism for acid catalyzed degradation is the rarely observed AAL1 which involves alkyl-nitrogen heterolysis. The driving force for the reaction appears to lie in the stability of the benzylic carbocation. The proposed mechanism for base catalyzed degradation is BAC2 which involves beta-lactam ring opening. The beta-lactam ring of DMP 777, a monolactam, appears to be as reactive as that in benzylpenicillin in the KOH controlled region where a similar mechanism of hydrolysis should be operative. A contributing factor to this increased reactivity may lie in the reduced basicity of the beta-lactam nitrogen making it a good leaving group. CONCLUSIONS: The degradation profile indicates that development of a solution dosage form of DMP 777 with adequate shelf-life stability at room temperature is feasible.